[Biological factors influencing infectious diseases transmitted by invasive species of mosquitoes]. / Éiologické factory ovlivnující vybrané infekcní nemoci prenásené invazivními druhy komáru.

Studies focused on arbovirus diseases transmitted by invasive species of mosquitoes have become increasingly significant in recent years, due to the fact that these vectors have successfully migrated to Europe and become established in the region. Mosquitoes, represented by more than 3 200 species, occur naturally worldwide, except in Antarctica. They feed on the blood of warm-blooded animals and by this route, they are capable of transmitting dangerous diseases. Some species can travel a distance of 10 km per night and can fly continuously for up to 4 hours at a speed of 1-2 km/h. Most species are active at night, in the evening or morning. It usually takes a mosquito female about 50 seconds to penetrate the skin of mammals and the subsequent blood meal usually takes about 2.5 minutes. Mosquitoes live for several weeks or months, depending on the environmental conditions. The VectorNet project is a European network of information exchange and sharing of data relating to the geographical distribution of arthropod vectors and transmission of infectious agents between human populations and animals. It aims at the development of strategic plans and vaccination policies which are the main tasks of this time, as well as the development and application of new disinfectants to control vector populations.

Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies.

In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.

Synthesis, antimicrobial evaluation and molecular modeling of 5-hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety.

In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.

Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease.

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 µm), butyrylcholinesterase (BChE IC50 : 2.4 µm) and MAO A (IC50 : 0.49 µm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 µm). Although its cytotoxic (IC50 : 5.5±0.4 µm) and hepatotoxic (IC50 : 1.22±0.11 µm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 µm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.

Synthesis and disinfection effect of the pyridine-4-aldoxime based salts.

A set of new quaternary ammonium compounds based on pyridine-4-aldoxime was synthesized, characterized with analytical data (NMR, EA, HPLC, MS) and tested for in vitro antimicrobial activity (antibacterial, antifungal) and cytotoxicity. Quaternary pyridinium-4-aldoxime salts with length of alkyl side chain from C8 to C20 and belonging to the group of cationic surfactants were investigated in this work. An HPLC experimental protocol for characterization of mixtures of all homologues has been found. Antimicrobial evaluation found that yeast-type fungi were most sensitive towards C14 and C16 analogues, whereas the C16 analogue was completely ineffective against filamentous fungi. Antibacterial assessment showed versatility of C14 and relatively high efficacy of C16 against G+ strains and C14 against G- strains. Notably, none of the studied compounds exceeded the efficacy and versatility of the benzalkonium C12 analogue, and benzalkonium analogues also exhibited lower cytotoxicity in the cell viability assay.